Project Summary/Abstract Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory. Pathological hallmarks of AD include amyloid-beta (A?) plaque deposition, neurofibrillary tangle (NFT) formation and the progressive loss of synapses and neurons. A growing literature has demonstrated immune activation in the brain, in particular activated microglia contribute to the onset and progression of AD by facilitating A? deposition and NFTs. There is no known cause for AD, however, several risk factors have been identified in the development of AD, including diabetes mellitus (DM) and advanced age. Patients with DM have a 1.5-4 fold increased risk of developing AD. The precise mechanisms by which DM increases the risk of AD is not known, but DM is associated with immune activation. As DM is more prevalent in aging populations it is likely these 2 risk factors combine in the pathogenesis of AD. We hypothesize that elevated inflammatory activation in DM, that is exacerbated by age is the primary driver of increased risk for AD, given inflammation exacerbates AD pathology. Separate data indicate the endogenous neurotransmitter GABA is capable of modulating activation of microglia and immune function and could serve a therapeutic role in DM patients at risk for AD, as well as AD patients comorbid with DM. In preliminary investigations we have demonstrated administration of an already FDA approved GABA receptor agonist in a DM animal model rescues learning and memory deficits, tau phosphorylation (NFT), and immune activation consistent with AD clinical populations and AD animal model systems. The research proposed will provide an opportunity to determine if the elevated inflammation associated with DM is a major contributor to AD pathology, in both males and females. Further, the experiments proposed will expand on our preliminary data to include evaluation of network function disrupted in AD, as well as determine if the rescue is mediated via direct modulation of microglia. Lastly, the data from the proposed research will elucidate the mechanisms underlying the rescue of AD related pathology and provide the necessary data to support the repurposing of an already FDA approved drug for use in a large subset of the AD population.